PROCESSES FOR THE PREPARATION OF IVABRADINE HCl POLYMORPHS

Abstract

Disclosed are new processes for the preparation of known polymorphs of ivabradine HCl, such processes being characterized by robust protocols suitable for industrial production.

1 . A process for the preparation of delta-d crystalline forms of ivabradine HCl, characterized from a powder X-ray diffractogram showing peaks at values of the diffraction angles 2 θ of 14.6, 15.3, 17.2, 18.1 and 21.4, which comprises:
 a) crystallization of crude ivabradine HCl in a solvent selected from acetonitrile, methyl ethyl ketone, C1-C5 alcohols, to give the respective crystalline solvate; 
 b) removal of the crystallization solvent by exposure of the crystalline solvate obtained in a), optionally subjected to a first drying, to an inert atmosphere with controlled relative humidity, followed by, drying; or alternatively 
 b′) removal of the crystallization solvent by exposure to a supercritical CO 2  flow. 
 
     
     
         2 . The process according to  claim 1 , wherein the C1-C5 alcohols are ethanol, isopropanol or 2-methyl-2-butanol. 
     
     
         3 . The process according to  claim 1  wherein the solvent is selected from ethanol and isopropanol. 
     
     
         4 . The process according to  claim 1 , wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C. 
     
     
         5 . The process according to  claim 1 , wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C. 
     
     
         6 . The process according to  claim 1 , wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl. 
     
     
         7 . The process according to  claim 1  wherein step b) is carried out on mixtures of delta forms of solvates of acetonitrile, ethanol, 2-methyl-2-butanol, isopropanol, methyl ethyl ketone optionally in mixture with delta-d forms of ivabradine HCl. 
     
     
         8 . The process according to  claim 1 , wherein step b) the delta-hydrated form of ivabradine HCl having KF between 5% and 10% is obtained. 
     
     
         9 . The process according to  claim 1 , wherein the removal of the crystallization solvent is carried out by treatment with supercritical CO 2  at a pressure between 70 bar and 140 bar at a temperature between 40° C. and 1.00° C. 
     
     
         10 . The process according to  claim 1 , wherein the delta-d form of ivabradine HCl is obtained having an acetonitrile content lower than 200 ppm or a content of ethanol or isopropanol or 2-methyl-2-butanol lower than 5000 ppm, and KF<0.5. 
     
     
         11 . The process according to  claims 2 , wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C. 
     
     
         12 . The process according to  claims 3 , wherein the crystalline solvate obtained in a) is subjected to a first drying under vacuum at a temperature between room temperature and 80° C. 
     
     
         13 . The process according to  claim 2 , wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C. 
     
     
         14 . The process according to  claim 3 , wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C. 
     
     
         15 . The process according to  claim 4 , wherein the removal of the crystallization solvent is carried out under inert atmosphere with relative humidity comprised between 15 and 65%, for a time between 5 and 36 hours, at a temperature between 10° C. and 40° C. 
     
     
         16 . The process according to  claim 2 , wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl. 
     
     
         17 . The process according to  claim 3 , wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl. 
     
     
         18 . The process according to  claim 4 , wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl. 
     
     
         19 . The process according to  claim 5 , wherein the crystalline solvate of ivabradine HCl prepared in a) comprises delta forms of solvates of acetonitrile, C1-C5 alcohols, or methyl ethyl ketone optionally in admixture with delta-d forms of ivabradine HCl. 
     
     
         20 . The process according to  claim 2 , wherein step b) is carried out on mixtures of delta forms of solvates of acetonitrile, ethanol, 2-methyl-2-butanol, isopropanol, methyl ethyl ketone optionally in mixture with delta-d forms of ivabradine HCl.